The proposed research is directed to a pharmacological and biochemical characterization of interactions between Delta 9-tetrahydrocannabinol (THC) and other drugs frequently used by humans. Our previous investigations have demonstrated that THC enhances the depressant effect of ethanol and that cross-tolerance between the two drugs develops. These phenomena were not related to changes in the disposition of either drug. The projected studies will correlate tolerance to, and physical dependence on, ethanol and THC, alone and in combination, with changes in RNA and DNA concentrations, and the incorporation of 14C-L-leucine into protein in vivo in the cerebral cortex, subcortex, cerebellum and ponsmedulla of the rat brain. Similarly, the acute and chronic interactive effects of THC and alcohol on the hypothalamic-pituitary-gonadal axis will be established in the rat. The serum and testes levels of luteinizing hormone, follicle-stimulating hormone, and testosterone will be determined by radioimmunoassay in addition to measurements of hepatic 14C-testosterone metabolism and testicular synthesis of the steroid. We have observed metabolic interactions between THC and other psychoactive drugs. Proposed experiments will examine the influence of drugs, selected for their potential interference with specific portions of the THC dispositional pathway in the rat. Compounds to be studied are: (1) morphine, imipramine, testosterone - which may compete with THC for hydroxylation and conjugation; (2) acetaminophen, salicylic acid, chloramphenicol - which are likely to compete for conjugation; (3) probenecid, ouabain, sulphobromophthalein (BSP) - which are likely to modify active biliary excretion; (4) sodium bicarbonate and ammonium chloride - which change urine pH and likely the excretion of acidic THC metabolites. Our studies have also shown that significant pharmacological interactions occur between THC, cannabinol (CBN) and cannabidiol (CBD). Future work will establish to what extent mutually-induced changes in cannabinoid metabolism and biliary excretion, organ distribution, and distribution into specific brain regions contribute to the pharmacological interactions.